An investigation on the MeCP2-early life stress interaction effects in anxiety sensitivity later in life in a mouse model of Rett syndrome.

Overview

Project Summary

Mutations in the methyl-CpG binding protein 2 gene (MECP2) are the primary cause of Rett syndrome (RTT), and to a lesser extent of other neurodevelopmental disorders such as X-linked mental retardation, autism, Angelman syndrome or schizophrenia. Anxiety is a prominent component of RTT behavioral phenotype, yet under investigated. Evidence from human and rodent models of RTT points to a role of MeCP2 in the modulation of the anxiety axis and thereby contribute to RTT’s, and eventually other MECP2-related disorders, susceptibility to anxiety and stress-related disorders. The occurrence of adverse events during the early-life period constitutes a major risk factor for the development of anxiety disorders. Early-life experiences are engraved in ‘permanent’ epigenetic marks, of which MeCP2 is a reader, that will impact on the response to stressful experiences later in life. Particularly, MeCP2 is involved in the reprogramming of the HPA axis reactivity, upon early-life stress, by regulating the expression of arginine vasopressin and corticotropin releasing hormone. In this project, we propose to investigate how the decreased functionality of MeCP2 early in life, as that seen in RTT patients and mouse models, will affect their vulnerability to develop anxiety and/or stress-related disorders later in life. Moreover, we will investigate the underlying neural circuits and molecular mechanisms. The knowledge derived from this pilot project could open new avenues for treatment, both pharmacological, specifically to expand to RTT the use of drugs targeting vasopressin system in anxiety, and non-pharmacological as early-life interventions that minimize stress could prove beneficial later in life.

Main Goals

The goal of the present project is to investigate how MeCP2 and MeCP2-environment interactions contribute to the modulation of neuronal circuits of anxiety and stress. To address this general goal, we have delineated the following specific aims:
 
Aim 1. In depth characterization of MeCP2 expression in anxiety- and stress-related brain regions during postnatal development and in adolescent wild-type animals, with or without early-life stress. Here, we will define key brain regions and critical windows of MeCP2 expression relevant in the interplay development period x environment.
 
Aim 2. To study the effects of MeCP2 and MeCP2-early life stress interaction on anxiety-related behaviors and physiology in the aftermath of acute stressors in the Mecp2-null males and Mecp2-heterozygous females;
 
Aim 3. To investigate the effects of MeCP2 and MeCP2-early life stress interaction on AVP and CRH neuronal populations and innervation in Mecp2-null males and Mecp2-heterozygous females;
 
Aim 4. To investigate the effects of MeCP2 and MeCP2-early life stress interaction on the methylation status and expression levels of Avp and Crh in the Pa nucleus of Mecp2-null males and Mecp2-heterozygous females;
 
Aim 5. To prove a direct role of AVP neuronal activation on the effects of early life stress on anxiety-related behavior later in life, using V1a and V1b receptor antagonists, using Mecp2-null males and Mecp2-heterozygous females.

Project Details